The 3rd World Congress onControversies to Consensus in Diabetes, Obesity and Hypertension (CODHy)Hilton Hotel, Prague, Czech Republic, May 13-16, 2010

Oral Presentations

ORAL ABSTRACTSObesity

IDENTIFICATION OF NEW TARGET FOR OBESITY AND TYPE II DIABETES TREATMENT BASED ON GENES ASSOCIATED WITH LEAN PHENOTYPE IN HUMAN AND VALIDATION OF THE TARGET BY GENE INACTIVATION IN MICEI. HaroshObeTherapy, Evry, France

Many obesity related genes have been proposed as targets for the treatment of obesity. However, these obesity genes do not provide efficient drug therapy for obesity treatment. This is mainly due to the redundancy of the biochemical pathway involved in obesity and the lack of specificity of the gene targets. It is therefore a challenge to identify crucial gene(s) targets involved in energy metabolism associated with “lean phenotype”. In order to identify these genes we have asked the following questions: - Is there any genetic disease associated with “lean phenotype”? - Is the phenotype associated with one gene (monogenic)? - Is the gene target tissue specific? - Is there any redundancy of the gene target? Congenital Enteropeptidase defficiency is an extremly rare pathology which answer to all these criteria. We have generated knock out transgenic mice for enteropeptidase which shows the same phenotype like in human. These data and in vivo preclinical data using per os small molecule for long term treatment (9 weeks) will be presented.

Background: PHEN/TPM is a low-dose, proprietary combination of phentermine (PHEN) and topiramate (TPM) for once-daily oral dosing. This pooled analysis of two Phase 3 studies evaluates weight loss over a 56 week period in overweight and obese subjects. Methods: 3678 subjects were randomly assigned to one of 3 dose levels of PHEN/TPM [15/92, 7.5/46, 3.75/23 mg] or placebo. All subjects were managed to standard of care. Results: The ITT population consisted of 74% women, 84% Caucasian, average age of 48 years. Subjects had a mean baseline weight of 107.4 kg, BMI of 38.4 kg/m2, and blood pressure of 126/80 mmHg. Mean weight loss at 56 weeks was 1.7%, 5.1%, 8.4%, and 10.6% (ITT-LOCF); and in subjects completing 56 weeks on treatment was 2.4%, 7.0%, 10.5%, and 13.7% for the placebo, 3.75/23 mg, 7.5/46 mg, and 15/92 mg groups, respectively (p<0.0001). Statistically significant improvements in all surrogate endpoints (SBP, DBP, waist circumference, and lipids) were seen in the 15/92 mg dose with greater than 10% weight loss. The lowest dose, 3.75/23 mg, met about half the endpoints with 5% weight loss. Conclusions: Consensus in the clinical community has been that modest weight loss of 5-7% leads to meaningful cardiovascular and metabolic benefits. This large, pooled analysis confirms these benefits, and demonstrates that weight loss of greater than 10% consistently yields greater benefit. Well-tolerated medical treatments that effect significant weight reduction and address obesity-related cardiovascular and metabolic risk may have significant benefits in terms of preventing future weight-related morbidity and mortality.

An impaired ability to store fatty acids (FA) in adipose tissue has been implicated in the pathogenesis of obesity related disease, via overexposure of lean tissues to FA, leading to formation of free radicals. We studied regional FA metabolism in skeletal muscle and adipose tissue in nine obese and six control subjects, and investigated the long term effects of the metabolic modulator trimetazidine on skeletal muscle, adipose tissue, and whole body substrate oxidation and metabolism. Fasting studies with positron emission tomography (PET) and [11C]-palmitate were performed in fifteen subjects; then, obese patients underwent one month of trimetazidine treatment. Indirect calorimetry and measurements of FA and glucose metabolism by means of [11C]-palmitate or [18F]-fluorodeoxyglucose and PET were performed before and after treatment. Obese subjects had higher skeletal muscle FA oxidation and uptake rates as compared with controls (6.6±1.1 vs. 2.6±0.4 and 10.7±1.3 vs. 5.8±0.8 µmol•min-1•kg-1, p<0.01) and markedly reduced FA uptake and esterification rates in adipose tissue (2.1±0.3 vs. 4.0±0.3 and 2.7±0.3 vs. 6.1±0.6 µmol•min-1•kg-1, p<0.001). Trimetazidine increased skeletal muscle FA esterification (p<0.01), and induced a tendency towards an increase in glucose phosphorylation (p=0.066). Our data document that human obesity is characterized by a defect in adipose tissue FA storage capability, which is accompanied by a (potentially compensatory) elevation in skeletal muscle FA oxidation. Trimetazidine induced a diversion of fatty acids from the oxidative to the non-oxidative pathway and an initial activation of glucose metabolism in skeletal muscle, which may explain the mechanism whereby this compound reduces oxidative stress.

Background: Insulin resistance and obesity represent the most important risk factors for development of NAFLD. Risk factors for development of fibrosis are age, BMI>30, glutamicoxaloacetic transaminase (AST)/glutamic-pyruvic transaminase (ALT)>1, and diabetes. The pathophysiology of NAFLD is described as a two hit model. The first hit is supposed to be the increase of free fatty acids in hepatocytes which results in a decrease of β-oxidation. Downregulation of beta-oxidation further aggravates accumulation of fatty acids. The second step includes all mechanisms contributing to the development of inflammation and fibrosis. The purpose of this study was to evaluate the impact of combination therapy with alpha-lipoic acid (ALA) and ursodeoxycholic acid (URSO) on the Non Alcoholic Fatty Liver Disease (NAFLD). Methods: ALA 400 mg/day plus URSO 300 mg/day (ALAURSO) was investigated in patients over a period of 6 months using a randomized, placebo- (PLA) controlled study with two parallel groups. Serum concentration of gamma- glutamyl transpeptidase (GGT), alanine aminotransferase (ALT) aspartate aminotransferase (AST), albumin (ALB), platelets (PLT) were measured at the beginning and at the end of the treatment. Moreover, we examined the AST/ALT rate and the NAFLD Fibrosis Score. Result: A total of 20 patients were randomly assigned to the two groups. ALA and URSO were safe and well tolerated in the only oral daily subministration. AST, ALT, GGT (p<0,001) showed a very significant difference between ALAURSO and PLA group. Besides, NAFLD Fibrosis Score underlined a significant reduction (p<0,04) in the ALAURSO group, while AST/ALT rate presented a moderate decline (p>0,05). Conclusion: ALAURSO therapy appears to reduce significantly AST, ALT, GGT, NAFLD Fibrosis Score and to improve AST/ALT rate value, especially being on a hypocaloric diet. These findings will be useful in patient selection in future clinical trials with ALAURSO in long term studies.

CHRONIC PERIODONTITIS AS A RISK FACTOR FOR DYSLIPIDAEMIC ATHEROGENESIS AND DIABETES: A BIDIRECTIONAL RELATIONSHIP?M. SooryKing's College London Dental Institute, London, UK

Positive associations between metabolic syndrome and dental plaque -associated inflammatory periodontal disease affecting supporting structures of teeth, have been reported. Oxidative stress-induced pathways lead to atherogenic dyslipidaemia, hypertension and raised plasma glucose levels which contribute to a prothrombotic and pro-inflammatory status and increased risk of type 2 diabetes mellitus. Sequelae of oxidative stress in response to lipopolysaccharide (LPS) a bacterial cell wall constituent result in elevated levels of markers of metabolic syndrome such as cytokines (e.g TNF-alpha), acute phase reactants (e.g C-reactive protein; CRP) and low density lipoprotein (LDL) in periodontal patients. Products of oxidative damage contribute to a pro-inflammatory state which could influence periodontitis and metabolic syndrome in a bidirectional manner; modulated by adipocytokines which mediate redox homeostasis and antioxidants which modulate these effects. Positive links between the body mass index and periodontal attachment loss are likely to be mediated by insulin resistance. There is a positive correlation between TNF-alphaƒzƒnCRP, LDL levels and periodontal disease. A pro-oxidant profile associated with hyperinflammatory trends seen in chronic periodontal disease is considered to have a significant systemic impact on atherogenic and prothrombotic features of metabolic syndrome and vice versa. Periodontal disease is often more severe in uncontrolled diabetic subjects who are known to be at risk for cardiovascular disease. Treatment of periodontitis has resulted in improved glycaemic control and reduced levels of acute phase markers of cardiovascular disease. Recognition of these reciprocal relationships between periodontal and systemic health is an important factor in coordinating health care and reducing systemic risk from periodontitis.

Objective: GLP-1 receptor agonists can induce antibodies, based on their homology to human GLP-1, that may decrease their efficacy. Of subjects taking exenatide, which has 53% homology, ~50% develop antibodies. We evaluated the frequency and effect of antibodies created by the once-daily human GLP-1 analog liraglutide, which has 97% homology. Methods: Prevalence of anti-liraglutide antibodies was assessed by radioimmunoassay in a pooled analysis from four phase 3 studies. All positive samples were tested for cross-reactivity to native GLP-1 and for in vitro neutralizing effect on liraglutide. The effect on hemoglobin A1c [HbA1c] was also determined. Subjects had end-of-treatment samples taken at least 5 days off drug (0.6 mg, 1.2 mg and 1.8 mg). Result: Anti-liraglutide antibodies appeared in 8.3% of subjects treated with 1.8 mg, 8.7% with 1.2 mg, and 9.2% with 0.6 mg. Overall, 102 (8.6%) of 1185 subjects generated antibodies. Of these, 12 had neutralizing antibodies in vitro, and 56 had antibodies that cross-reacted with native GLP-1. Antibody titers ranged from 1.6-10.7%B/T (% Bound/Total) with a mean of 3.28%B/T. In the 1.8 mg arm, antibody-positive subjects had a mean HbA1c reduction of -1.1%, while those negative had -1.2%. In the 1.2 mg arm, the reduction was -1.3% vs -1.2%, respectively. In the 0.6 mg arm, no difference occurred. Nine antibody-positive subjects reported injection site reactions, but none were withdrawn due to these events. Conclusion: Consistent with liraglutide’s high homology to native GLP-1, the prevalence of anti-liraglutide antibodies was <10%, with low titers that did not affect efficacy.

BACKGROUND: Recent studies have indicated a relationship between type 2 diabetes and sleep-disordered breathing (SDB). However, it remains unknown whether obesity is an independent risk factor for SDB and whether other risk factors than obesity may exist for SDB in subjects with type 2 diabetes. OBJECTIVE: We evaluated the prevalence of SDB and assessed the clinical characteristics of SDB, especially in relation to cardiac autonomic dysfunction in Japanese subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS: We measured oxygen desaturations index (ODI) by nocturnal pulse oximetry of 369 consecutive Japanese subjects with type 2 diabetes (aged 40-79 years), who were admitted to our hospital. SDB was defined by 4%ODI level of 5 or more events per hour. RESULTS: The prevalence of SDB in all subjects with type 2 diabetes was 24.5%. The diabetic subjects with SDB had higher body mass index (BMI), heart rate (HR) and neck circumference than the diabetic subjects without SDB. In the nonobese diabetic group (BMI <25 kg/m2), subjects with SDB had significantly lower coefficient of variation of R-R intervals (CVRR) than those without SDB. Multiple regression analysis revealed that CVRR was a significant factor for SDB in nonobese subjects with type 2 diabetes, whereas systolic blood pressure and HR were significant factors for SDB in obese subjects with type 2 diabetes. CONCLUSIONS: This study shows that SDB is highly prevalent in Japanese subjects with type 2 diabetes, and that cardiac autonomic dysfunction is associated with SDB in nonobese subjects with type 2 diabetes.

Objective: Steady state hyperinsulinaemia during a hyperinsulinaemic euglycaemic clamp stimulates endothelium-dependent vasomotion and vasodilation as well as capillary recruitment, which contribute to increased glucose uptake; these phenomena have been shown to be blunted in obesity. This study was designed to investigate whether similar results can be obtained during dynamic hyperinsulinaemia. Methods: A randomised, placebo-controlled trial was performed in 18 healthy and 13 obese subjects, to examine the effects of a glucose drink (75 g glucose), a 495-kcal liquid mixed meal (60% carbohydrates, 25% proteins, 15% fat) or placebo (tap water) on microvascular function. Skin endothelium-(in)dependent vasodilatation was evaluated by laser Doppler flowmetry (LDF) with iontophoresis of acetylcholine and sodium nitroprusside. Vasomotion was examined by Fourier analysis of the LDF signal. Results: Both the glucose drink and the liquid mixed meal, but not placebo, induced hyperinsulinaemia. The levels of hyperinsulinaemia were higher in obese compared to healthy subjects (P<0.05). Compared to placebo, vasomotion analysis showed increased endothelial activity in healthy subjects following the glucose drink (P<0.05) and meal drink (P=0.001). Compared to healthy subjects, a significant decrease of endothelial activity was found in obese subjects following the meal drink (P<0.05). No changes in endothelium-(in)dependent vasodilatation following iontophoresis of acetylcholine or sodium nitroprusside were found in either group. Conclusion: A glucose load and a mixed meal, which are accompanied by non-steady state hyperinsulinaemia, increase endothelial vasomotion in healthy individuals. These responses are blunted in obese subjects. These data suggest impairment of microvascular function in the postprandial state in obese individuals.

Background and Aim: It was previously suggested that hypertriglyceridemic waist (HTgW) phenotype (waist girth ≥90 cm in men and ≥85 cm in women, and triglyceride (Tg) levels ≥2.0 mmol/l) could identify visceral obesity and higher risk for atherosclerosis, but the relationship between HTgW phenotype and different atherosclerosis risk factors has not yet been elucidated. The aim of this study was to compare (a) insulin sensitivity (IS), (b) cholesterol and its subfraction levels and (c) LDL particle size between 40 patients with HTgW (group A; waist: 101.2+/-1.2cm; Tg:2.7+/-0.12 mmol/l) and 50 patients without HTgW (group B; waist: 99.8+/- 1.7cm; Tg:1.4+/-0.07 mmol/l). Methods: IS levels were determined by minimal model analysis (Si), total cholesterol (Ch), HDL-Ch, LDL-Ch and Tg levels by enzymatic methods and the LDL particle diameter by gradient gel electrophoresis. Results: We found significantly lower Si values in group A vs B (2.53+/-0.41 vs 5.90+/-1.04 min-1/mU/lx10(4); p<0.01). Simultaneously, HDL-Ch level was significantly lower in group A vs B (0.98+/-0.04 vs 1.14+/-0.05 mmol/l; p<0.01) while we could not find significant differences in total and LDL-Ch. However, the mean LDL particle size levels was significantly lower in group A vs B (26.08+/-0.16 vs 26.73+/-0.17 nm; p<0.05). Conclusions: Our results signify that presence of HTgW phenotype is strongly associated with insulin resistance together with a decrease in LDL particle diameter but not with changes in total LDL-Ch levels. The results imply that in this phenotype insulin resistance might be exerting its atherogenic effect on the level of the changes in LDL particle size.